Enamine system, reduction

Reduction of the enamine system of an aminostilbene by sodium in liquid ammonia 189) and of a 17-enaminosteroid by aluminum and mercuric chloride in alcohol 560) have also been reported. 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

The /3-position of an enamine system is much more difficult to meta-late than the a-position because of the higher electron density on the /3-carbon, and so additional activation, or stronger base systems, are often required for efficient reaction. Thus, successful /3-lithiation of the 3-(phenylthio)enamine of morpholine can be achieved because of the stabilizing effect of the sulfur atom, whereas reductive lithiation of the same species can be achieved with lithium napthalenide or lithium in liquid ammonia (Scheme 131) [82JCR(M)621,82JCR(S)48]. Similar /3-lithioenam-... 

The reduction of isoquinolinium ions has been extensively investigated with borohydride and aluminum hydride ions. The use of boro-hydride ion in a protonic solvent normally leads to the formation of 1,2,3,4-tetrahydroisoquinolines, whereas the reduction with aluminum hydride ion in an aprotic medium generally gives a 1,2-dihydroiso-quinoline. This 1,2-dihydroisoquinoline contains an enamine system and may undergo further reaction on treatment with acid. The 1,2-and 3,4-dihydroisoquinolines as well as isoquinolinium ions are reduced by the borohydride ion in a protonic medium to the 1,2,3,4-tetrahydroisoquinolines. 

Cyclization of an indolylethyl-tetrahydropyridine derivative is also a key stage in an extremely brief and elegant synthesis of the yohimbine ring system and a number of ajmalicinoid bases by Wenkert and his collaborators.78 Thus, internal nucleophilic attack by enolate anion at the y-position to the nitrogen atom in (122) gave a tetrahydropyridine derivative which readily cyclized to the pentacyclic enamine (123), reduction of which gave (db)-pseudoyohimbone (124) (Scheme 11). 

Qulnolinium salts (68 Scheme 15) can undergo attack at either the 2- or 4-position. The former normally predominates and the latter leads to 1,2,3,4-tetrahydroquinolines (69). 3-Substituents generally produce mixtures of the 1,2- and 1,4-dihydro adducts. Isoquinolinium salts (70 Scheme 15) produce both 1,2-dihydrolsoqulnolines (71) and 1,2,3,4-tetrahydroisoquinolines (72). Reduction in protlc solvents normally produces the tetrahydro adducts, in anhydrous pyridine or dimethylformamide the reduction generally stops at the 1,2-dihydroisoquinoline. Reaction of the enamine system of 1,2-dihydroisoqui-nollnes with electrophiles has been used as a method for generation of 4-substituted isoquinolines. 

Quinolinium and isoquinolinium salts form predominantly 1,2-dihydro products with LAH reductions in aprotic solvents. With the latter the enamine system revealed is amenable to functionalization... 

The reduction of isoquinolinium salts in aprotic solvents with LAH leads to the formation of 1,2-dihydroisoquinolines (195), in which the enamine system can undergo subsequent reaction with electrophiles. This type of reactivity has been exploited in the synthesis of alkaloids. ... 

The lithium-propylamine reducing system has been found capable of reducing julolidine to a mixture of enamines . Selective reduction of lactams with... 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

The use of enamines as protective groups seems largely to be confined to steroid chemistry, where they serve (in their protonated form) to protect the A-B enone system from bromination and reduction. A large body of literature exists on the preparation and chemistry of enamines, which are easily hydrolyzed with water or aqueous acid. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

Similar reactivity and regioselectivity is observed with the parent system, 1,2,4-triazine (eq 2) Reduction of this process to a catalytic Diels-Alder reaction with in situ generation of the pyrrolidine enamine does... 

The reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

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